PI3K/AKT/mTOR通路
虚拟筛选
化学
药物发现
蛋白激酶B
mTOR抑制剂的发现与发展
对接(动物)
IC50型
激酶
码头
计算生物学
细胞生长
信号转导
药理学
生物化学
生物
体外
医学
护理部
作者
Yang Yang,Rujue Peng,Zhenjie Cheng,Mengting Yu,Li Fu,Xufei Zhang,Pengwu Zheng,Wufu Zhu,Linxiao Wang,Shan Xu
标识
DOI:10.1016/j.molstruc.2023.137425
摘要
The dysregulation of the PI3K/Akt/mTOR signaling pathway is one of the crucial pathways, leading to cancer development. mTOR (Rapamycin/mammalian target of rapamycin) participates in various intracellular signaling processes, regulating cellular metabolism, proliferation, and apoptosis. Numerous mTOR inhibitors have entered clinical research but are not yet on the market. There is an urgent need to develop a drug discovery strategy to accelerate the process. This study applied a virtual screening strategy to identify an mTOR inhibitor with potential inhibitory activity against mTOR. Firstly, we employed the Vina software to dock active and inactive datasets with two proteins (4L23 and 4JT6). The sensitive protein which is based on the docking results and ROC curve analysis is selected. Then, using the KNIME molecular screening program, virtual screening, cluster analysis, and binding model analysis, the 14 hit compounds are identified. Thirdly, through kinase assay and anti-proliferative activity evaluation, the hit compound AK-968/13030056 was ultimately confirmed. Finally, we conducted molecular docking studies and anti-tumor activity research on this compound. The inhibition rate of this compound on mTOR kinase was 70.62 %, exhibiting the strongest inhibitory activity against MCF-7 cells with an IC50 of 7.49 ± 0.87 μM. Subsequently, the biocompatibility of this compound was confirmed through hemolysis testing. Pharmacological experiments including AO staining, JC-1 assays, cell migration, and quantitative real-time PCR analysis also validated its anti-tumor activity. This study has developed a precise and rapid drug discovery strategy, successfully identifying a novel compound with inhibitory activity against the mTOR protein.
科研通智能强力驱动
Strongly Powered by AbleSci AI